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4EI4

JAK1 kinase (JH1 domain) in complex with compound 20

Summary for 4EI4
Entry DOI10.2210/pdb4ei4/pdb
Related4EHZ 4F08 4F09
DescriptorTyrosine-protein kinase JAK1, (1R,3R)-3-(2-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(8H)-yl)cyclohexanol (3 entities in total)
Functional Keywordsprotein kinase, phospho-transfer catalyst, transferase-transferase inhibitor complex, transferase/transferase inhibitor
Biological sourceHomo sapiens (human)
Cellular locationEndomembrane system; Peripheral membrane protein: P23458
Total number of polymer chains2
Total formula weight70033.85
Authors
Eigenbrot, C.,Steffek, M. (deposition date: 2012-04-04, release date: 2012-07-04, Last modification date: 2024-11-27)
Primary citationZak, M.,Mendonca, R.,Balazs, M.,Barrett, K.,Bergeron, P.,Blair, W.S.,Chang, C.,Deshmukh, G.,Devoss, J.,Dragovich, P.S.,Eigenbrot, C.,Ghilardi, N.,Gibbons, P.,Gradl, S.,Hamman, C.,Hanan, E.J.,Harstad, E.,Hewitt, P.R.,Hurley, C.A.,Jin, T.,Johnson, A.,Johnson, T.,Kenny, J.R.,Koehler, M.F.,Bir Kohli, P.,Kulagowski, J.J.,Labadie, S.,Liao, J.,Liimatta, M.,Lin, Z.,Lupardus, P.J.,Maxey, R.J.,Murray, J.M.,Pulk, R.,Rodriguez, M.,Savage, S.,Shia, S.,Steffek, M.,Ubhayakar, S.,Ultsch, M.,van Abbema, A.,Ward, S.I.,Xiao, L.,Xiao, Y.
Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.
J.Med.Chem., 55:6176-6193, 2012
Cited by
PubMed Abstract: Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.
PubMed: 22698084
DOI: 10.1021/jm300628c
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.22 Å)
Structure validation

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